Many clinical conditions, deficiencies, and disease states can be remedied or alleviated by supplying to the patient a factor or factors produced by living cells or removing from the patient deleterious factors which are metabolized by living cells. In many cases, these factors can restore or compensate for the impairment or loss of organ or tissue function. Examples of disease or deficiency states whose etiologies include loss of secretory organ or tissue function include (a) diabetes, wherein the production of insulin by pancreatic islets of Langerhans is impaired or lost; (b) hypoparathyroidism, wherein the loss of production of parathyroid hormone causes serum calcium levels to drop, resulting in severe muscular tetany; (c) Parkinsonism, wherein dopamine production is diminished; and (d) anemia, which is characterized by the loss of production of red blood cells secondary to a deficiency in erythropoietin. The impairment or loss of organ or tissue function may result in the loss of additional metabolic functions. For example, in fulminant hepatic failure, liver tissue is rendered incapable of removing toxins, excreting the products of cell metabolism, and secreting essential products, such as albumin and Factor VIII. Bontempo, F. A., et al., Blood 69:1721 (1987).
In other cases, these factors are biological response modifiers, such as lymphokines or cytokines, which enhance the patient's immune system or act as anti-inflammatory agents. These can be particularly useful in individuals with a chronic parasitic or infectious disease, and may also be useful for the treatment of certain cancers. It may also be desirable to supply trophic factors to a patient, such as nerve growth factor or insulin-like growth factor-one or -two (IGF1 or IGF2).
In many disease or deficiency states, the affected organ or tissue is one which normally functions in a manner responsive to fluctuations in the levels of specific metabolites, thereby maintaining homeostasis. For example, the parathyroid gland normally modulates production of parathyroid hormone (PTH) in response to fluctuations in serum calcium. Similarly, .beta. cells in the pancreatic islets of Langerhans normally modulate production of insulin in response to fluctuations in serum glucose. Traditional therapeutic approaches to the treatment of such diseases cannot compensate for the responsiveness of the normal tissue to these fluctuations. For example, an accepted treatment for diabetes includes daily injections of insulin. This regimen cannot compensate for the rapid, transient fluctuations in serum glucose levels produced by, for example, strenuous exercise. Failure to provide such compensation may lead to complications of the disease state; this is particularly true in diabetes. Jarret, R. J. and Keen J., Lancet (2):1009 (1976).
Accordingly, many investigators have attempted to reconstitute organ or tissue function by transplanting whole organs, organ tissue, or cells which provide secreted products or affect metabolic functions. Moreover, transplantation can provide dramatic benefits but is limited in its application by the relatively small number of organs suitable and available for grafting. In general, the patient must be immunosuppressed in order to avert immunological rejection of the transplant, which results in loss of transplant function and eventual necrosis of the transplanted tissue or cells. In many cases, the transplant must remain functional for a long period of time, even for the remainder of the patient's lifetime. It is both undesirable and expensive to maintain a patient in an immunosuppressed state for a substantial period of time.
A desirable alternative to such transplantation procedures is the implantation of cells or tissues within a physical barrier which will allow diffusion of nutrients, waste materials and secreted products, but block the cellular and molecular effectors of immunological rejection. A variety of devices which protect tissues or cells producing a selected product from the immune system have been explored. These include extravascular diffusion chambers, intravascular diffusion chambers, and implantation of microencapsulated cells. Scharp, D. W., et al. World J. Surg. 8:221 (1984). These devices were envisioned as providing a significant advance in the field of transplantation, as they would alleviate the need to maintain the patient in an immunosuppressed state, and would thereby allow many more patients to receive restorative or otherwise beneficial transplants by allowing the use of donor cells or tissue which could not have been used with the conventional transplantation techniques. However, none of these approaches have been satisfactory for providing long-term transplant function. A method of delivering appropriate quantities of needed substances, such as enzymes and hormones, or of providing other needed mebaolic functions, for an extended period of time is still unavailable and would be very advantageous to those in need of long-term treatment.
A number of different techniques have been used for microencapsulation of living cells. For example, live mammalian cells have been microencapsulated in calcium alginate gels and then coated with polylysine and/or polyethylene imine. O'Shea, G. M., et al., Biochim. Biophys. Acta., 804:133 (1984).
In prior microcapsules, cells in the core of the microcapsule where linked to the jacket or coating by ionic bonds between oppositely charged polymers. See e.g., Raj, U.S. Pat. No. 4,744,933 and Lim and Sun, U.S. Pat. Nos. 4,352,833 and 4,409,331.
The use of water insoluble, hydrophilic polyacrylates has been disclosed for the microencapsulation of mammalian cells. Sefton, M. W., et al., Biochim. Biophys. Acta., 717:473 (1982). Further modification of this technique includes encapsulation of such cells in a water insoluble polyacrylate by co-axial extrusion and interface precipitation. Sugamori, M. E., et al., Trans. Am. Soc. Atrif. Intern. Organs, 35:791 (1989). The system discloses an inner and outer barrel with the cells flowing through the inner barrel and polymer through outer barrel. Polymer-coated droplets formed at the tip of the extruder are forced off by a co-axial airstream and fall into a precipitation bath. There, microcapsules are formed having cores of the living cells within a polymer coating.